There is a great need for safer general anesthetics for use in critically ill patients, and particularly for patients with sepsis. (R)-Etomidate possesses many properties that would make it an ideal anesthetic agent (e.g. high anesthetic potency, lesser effects on cardiovascular function and higher therapeutic index than other agents) if it were not such a potent inhibitor of adrenocortical function.
Etomidate is an imidazole-based intravenous hypnotic that is frequently used to induce anesthesia in the elderly and critically ill because it maintains hemodynamic stability better than other anesthetic agents.1-3 Unfortunately, etomidate also produces adrenocortical suppression, a side effect that can persist for days after etomidate administration.4-8 This potentially deadly side effect has caused clinicians to abandon the use of etomidate infusions and led to concerns regarding the administration of even a single intravenous (IV) bolus dose for anesthetic induction.9-11 In a previous study, the inventors developed methoxycarbonyl etomidate (MOC-etomidate) as the prototypical member of a new class of “etomidate esters” that, similar to remifentanil and esmolol, contains a metabolically-labile ester moiety that is rapidly hydrolyzed by esterases (FIG. 1).12 Inventors showed that MOC-etomidate is rapidly hydrolyzed in rat blood and human liver s9 fraction and produces hypnosis and adrenocortical suppression of extremely short duration when administered to rats as an IV bolus.12,13 
A key feature of soft drugs is that their metabolic stabilities and durations of action must fall within an optimal range to be clinically useful.14 A drug that is too rapidly metabolized and short-acting will require the administration of impractically large quantities to maintain a therapeutic effect and may produce metabolite concentrations sufficient to produce undesirable side effects when given for a prolonged period of time. Conversely, a drug that is too slowly metabolized and long acting will have pharmacokinetic properties that are not meaningfully different from the metabolically stable “hard” drug from which it was derived.
Because esterase activity varies significantly among species, it is difficult to predict from small animal studies whether any particular soft drug's pharmacokinetic profile will fall within the optimal range when administered to humans.15 